Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Impact of COVID-19 pandemic on multidrug resistant gram positive and gram negative pathogens: A systematic review.

BACKGROUND: There is paucity of data describing the impact of COVID-19 pandemic on antimicrobial resistance. This review evaluated the changes in the rate of multidrug resistant gram negative and gram positive bacteria during the COVID-19 pandemic. METHODS: A search was conducted in PubMed, Science Direct, and Google Scholar databases to identify eligible studies. Studies that reported the impact of COVID-19 pandemic on carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase inhibitor (ESBL)-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Pseudomonas aeruginosa (CPE) were selected. Studies published in English language from the start of COVID-19 pandemic to July 2022 were considered for inclusion. RESULTS: Thirty eligible studies were selected and most of them were from Italy (n = 8), Turkey (n = 3) and Brazil (n = 3). The results indicated changes in the rate of multidrug resistant bacteria, and the changes varied between the studies. Most studies (54.5%) reported increase in MRSA infection/colonization during the pandemic, and the increase ranged from 4.6 to 170.6%. Five studies (55.6%) reported a 6.8-65.1% increase in VRE infection/colonization during the pandemic. A 2.4-58.2% decrease in ESBL E. coli and a 1.8-13.3% reduction in ESBL Klebsiella pneumoniae was observed during the pandemic. For CRAB, most studies (58.3%) reported 1.5-621.6% increase in infection/colonization during the pandemic. Overall, studies showed increase in the rate of CRE infection/colonization during the pandemic. There was a reduction in carbapenem-resistant E. coli during COVID-19 pandemic, and an increase in carbapenem-resistant K. pneumoniae. Most studies (55.6%) showed 10.4 - 40.9% reduction in the rate of CRPA infection during the pandemic. CONCLUSION: There is an increase in the rate of multidrug resistant gram positive and gram negative bacteria during the COVID-19 pandemic. However, the rate of ESBL-producing Enterobacteriaceae and CRPA has decrease during the pandemic. Both infection prevention and control strategies and antimicrobial stewardship should be strengthen to address the increasing rate of multidrug resistant gram positive and gram negative bacteria.

Predictors of clinical evolution of SARS-CoV-2 infection in hematological patients: A systematic review and meta-analysis.

Main aim of this systematic review is to quantify the risk and identify predictors of clinical evolution of SARS-CoV-2 in hematological patients compared to different control populations. Two independent reviewers screened the literature assessing clinical outcomes of SARS-CoV-2 infection in adult patients with active hematological malignancies published up to June 2021. Primary outcome was COVID-19 related mortality, secondary outcomes were hospital and intensive-care admission, mechanical ventilation (MV), and thromboembolic events. Variables related to study setting, baseline patients' demographic, comorbidities, underlying hematological disease, ongoing chemotherapy, COVID-19 presentation, and treatments were extracted. A total of 67 studies including 10,061 hematological patients and 111,143 controls were included. Most of the studies were retrospective cohorts (51 studies, 76%) and only 19 (13%) provided data for a control group. A significant increased risk of clinical progression in the hematological population compared to the controls was found in terms of COVID-19 related mortality (OR, 2.12; 95% CI, 1.77-2.54), hospitalization (OR, 1.98; 95% CI, 1.15-3.43), intensive-care admission (OR, 1.77; 95% CI, 1.38-2.26), and MV (OR, 2.17; 95% CI, 1.71-2.75). The risk remained significantly higher in the subgroup analysis comparing hematological patients versus solid cancer. Meta-regression analysis of uncontrolled studies showed that older age, male sex, and hypertension were significantly related to worse clinical outcomes of COVID-19 in hematological population. Older age and hypertension were found to be associated also to thromboembolic events. In conclusion, hematological patients have a higher risk of COVID-19 clinical progression compared to both the general population and to patients with solid cancer.

Healthcare-associated infections in Africa: a systematic review and meta-analysis of point prevalence studies.

BACKGROUND: There is limited data to describe the point-prevalence of healthcare-associated infections (HAIs) among patients at a regional level in Africa. This study estimated the pooled prevalence of HAIs and described the distribution of HAIs as well as the pathogens identified from African studies. METHODS: PubMed, Scopus and Google Scholar databases were searched to find point-prevalence studies of HAIs in Africa. Studies conducted in Humans that reported the prevalence of HAIs among hospitalized patients and published in English language from January 2010 to March 2022 were selected. Longitudinal studies of HAIs and unpublished studies were excluded. The reference list of the selected studies was checked to find additional studies. A meta-analysis was conducted using RevMan 5.4 and the pooled prevalence of HAIs was determined using a random effect model. RESULTS: Of the 6094 articles identified from the databases, fifteen eligible articles were selected. The studies were conducted in the North, South, East and West African regions with Tunisia (n = 4) and South Africa (n = 2) having the highest number of studies. Most of the studies (n = 12, 80.0%) had good quality. The pooled prevalence of HAIs was 12.76% (95% confidence interval [CI] 10.30-15.23) with a high degree of heterogeneity (I2 = 90.0%). The prevalence of HAIs varied between wards with the highest rate found in the ICU (25.2%-100%), followed by neonatal ICU/ward (7.0%-53.6%) and paediatric medical ward (2.7%-33.0%). Surgical site infection was the most common HAIs and accounted for 41.6% of all HAIs (95% CI 23.55-59.80), followed by bloodstream infection (17.07%, 95% CI 11.80-22.33) and respiratory tract infections/pneumonia (17.04%, 95% CI 13.21-20.87). Recent hospitalization (adjusted odds ratio [AOR]: 4.17, 95% CI 1.85-9.41), presence of peripheral vascular catheter (AOR: 2.87, 95% CI 1.54-5.36) and having diabetes mellitus (AOR: 2.46, 95% CI 1.45-4.17) were the strongest predictors of HAIs in Africa. Only 37.9% of HAIs had documented positive microbiological culture result with gram negative bacteria including Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii and Citrobacter been the most common microorganisms and accounted for 40%-100% of the pathogens. CONCLUSIONS: The pooled point-prevalence of HAIs in Africa is more than two times higher than the rate reported in developed countries. The prevalence varied between the countries and was highest in the ICU and neonatal ICU/ward. Surgical site infection and bloodstream infection were the most common HAIs reported in African studies. Recent hospitalization, presence of peripheral vascular catheter and having diabetes mellitus were the strongest predictors of HAIs in African studies. Most of the HAIs are preventable with appropriate infection control measures and antimicrobial stewardship. Additional studies are needed especially in the Central African region. Future studies should be designed using standardized protocol and standardized definition to reduce heterogeneity among the studies.

Association of Patients' Epidemiological Characteristics and Comorbidities with Severity and Related Mortality Risk of SARS-CoV-2 Infection: Results of an Umbrella Systematic Review and Meta-Analysis.

The objective of this study was to assess the association between patients' epidemiological characteristics and comorbidities with SARS-CoV-2 infection severity and related mortality risk. An umbrella systematic review, including a meta-analysis examining the association between patients' underlying conditions and severity (defined as need for hospitalization) and mortality of COVID-19, was performed. Studies were included if they reported pooled risk estimates of at least three underlying determinants for hospitalization, critical disease (ICU admission, mechanical ventilation), and hospital mortality in patients diagnosed with SARS-CoV-2 infection. Evidence was summarized as pooled odds ratios (pOR) for disease outcomes with 95% confidence intervals (95% CI). Sixteen systematic reviews investigating the possible associations of comorbidities with severity or death from COVID-19 disease were included. Hospitalization was associated with age > 60 years (pOR 3.50; 95% CI 2.97-4.36), smoking habit (pOR 3.50; 95% CI 2.97-4.36), and chronic pulmonary disease (pOR 2.94; 95% CI 2.14-4.04). Chronic pulmonary disease (pOR 2.82; 95% CI 1.92-4.14), cerebrovascular disease (pOR 2.74; 95% CI 1.59-4.74), and cardiovascular disease (pOR 2.44; 95% CI 1.97-3.01) were likely to be associated with increased risk of critical COVID-19. The highest risk of mortality was associated with cardiovascular disease (pOR 3.59; 95% CI 2.83-4.56), cerebrovascular disease (pOR 3.11; 95% CI 2.35-4.11), and chronic renal disease (pOR 3.02; 95% CI 2.61-3.49). In conclusion, this umbrella systematic review provides a comprehensive summary of meta-analyses examining the impact of patients' characteristics on COVID-19 outcomes. Elderly patients and those cardiovascular, cerebrovascular, and chronic renal disease should be prioritized for pre-exposure and post-exposure prophylaxis and early treatment.

Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.

OBJECTIVES: More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain. METHODS: A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis. RESULTS: A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins. CONCLUSIONS: This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.

Evaluation of the Kinetics of Antibody Response to COVID-19 Vaccine in Solid Organ Transplant Recipients: The Prospective Multicenter ORCHESTRA Cohort.

Previous studies assessing the antibody response (AbR) to mRNA COVID-19 vaccines in solid organ transplant (SOT) recipients are limited by short follow-up, hampering the analysis of AbR kinetics. We present the ORCHESTRA SOT recipients cohort assessed for AbR at first dose (t0), second dose (t1), and within 3 ± 1 month (t2) after the first dose. We analyzed 1062 SOT patients (kidney, 63.7%; liver, 17.4%; heart, 16.7%; and lung, 2.5%) and 5045 health care workers (HCWs). The AbR rates in the SOTs and HCWs were 52.3% and 99.4%. The antibody levels were significantly higher in the HCWs than in the SOTs (p < 0.001). The kinetics showed an increase (p < 0.001) in antibody levels up to 76 days and a non-significant decrease after 118 days in the SOT recipients versus a decrease up to 76 days (p = 0.02) and a less pronounced decrease between 76 and 118 days (p = 0.04) in the HCWs. Upon multivariable analysis, liver transplant, ≥3 years from SOT, mRNA-1273, azathioprine, and longer time from t0 were associated with a positive AbR at t2. Older age, other comorbidities, mycophenolate, steroids, and impaired graft function were associated with lower AbR probability. Our results may be useful to optimize strategies of immune monitoring after COVID-19 vaccination and indications regarding timing for booster dosages calibrated on SOT patients' characteristics.

Persistence of SARS-CoV-2 Infection in Severely Immunocompromised Patients With Complete Remission B-Cell Lymphoma and Anti-CD20 Monoclonal Antibody Therapy: A Case Report of Two Cases.

Immunosuppressant conditions such as hematological malignancies increase the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It has been described in the literature that patients on anti-CD20 maintenance therapies for lymphoid malignancies are susceptible to having recurrent flares together with viral replication or reinfections, although these cases are scarce. These patients are not well represented in randomized controlled trials, and as a consequence, the evidence for the use of certain treatments in this scenario is lacking. We present two cases of patients with B-cell lymphoma on remission and treated with rituximab on maintenance. They developed at least 1 flare of coronavirus disease 2019 (COVID-19) after acute infection and always after receiving rituximab. RT-PCR was positive in the nasopharyngeal swab and also in plasma. Patients were treated during flares with remdesivir, hyperimmune plasma, and corticosteroids. These two cases showed the unresolved problem of COVID-19 in immunosuppressant patients and showed that despite the vast amount of information available on SARS-CoV-2, information in this subgroup of patients is lacking.

Clinical outcome in solid organ transplant recipients affected by COVID-19 compared to general population: a systematic review and meta-analysis.

BACKGROUND: A significant increased risk of complications and mortality in immunocompromised patients affected by COVID-19 has been described. However, the impact of COVID-19 in solid organ transplant (SOT) recipients is an issue still under debate, due to conflicting evidence that has emerged from different observational studies. OBJECTIVES: We performed a systematic review with a meta-analysis to assess the clinical outcome in SOT recipients with COVID-19 compared with the general population. DATA SOURCES: PubMed-MEDLINE and Scopus were independently searched until 13 October 2021. STUDY ELIGIBILITY CRITERIA: Prospective or retrospective observational studies comparing clinical outcome in SOT recipients versus general populations affected by COVID-19 were included. The primary endpoint was 30-day mortality. PARTICIPANTS: Participants were patients with confirmed COVID-19. INTERVENTIONS: Interventions reviewed were SOTs. METHODS: The quality of the included studies was independently assessed with the Risk of Bias in Non-randomized Studies of Interventions tool for observational studies. The meta-analysis was performed by pooling ORs retrieved from studies providing adjustment for confounders using a random-effects model with the inverse variance method. Multiple subgroups and sensitivity analyses were conducted to investigate the source of heterogeneity. RESULTS: A total of 3501 articles were screened, and 31 observational studies (N = 590 375; 5759 SOT recipients vs. 584 616 general population) were included in the meta-analyses. No difference in 30-day mortality rate was found in the primary analysis, including studies providing adjustment for confounders (N = 17; 3752 SOT recipients vs. 159 745 general population; OR: 1.13; 95% CI, 0.94-1.35; I2 = 33.9%). No evidence of publication bias was reported. A higher risk of intensive care unit admission (OR: 1.56; 95% CI, 1.03-2.63) and occurrence of acute kidney injury (OR: 2.50; 95% CI, 1.81-3.45) was found in SOT recipients. CONCLUSIONS: No increased risk in mortality was found in SOT recipients affected by COVID-19 compared with the general population when adjusted for demographic and clinical features and COVID-19 severity.

Impact of early interferon-ß treatment on the prognosis of patients with COVID-19 in the first wave: A post hoc analysis from a multicenter cohort.

BACKGROUND: Interferon-ß is an attractive drug for repurposing and use in the treatment of COVID-19, based on its in vitro antiviral activity and the encouraging results from clinical trials. The aim of this study was to analyze the impact of early interferon-ß treatment in patients admitted with COVID-19 during the first wave of the pandemic. METHODS: This post hoc analysis of a COVID-19@Spain multicenter cohort included 3808 consecutive adult patients hospitalized with COVID-19 from 1 January to 17 March 2020. The primary endpoint was 30-day all-cause mortality, and the main exposure of interest was subcutaneous administration of interferon-ß, defined as early if started ≤ 3 days from admission. Multivariate logistic and Cox regression analyses were conducted to identify the associations of different variables with receiving early interferon-ß therapy and to assess its impact on 30-day mortality. A propensity score was calculated and used to both control for confounders and perform a matched cohort analysis. RESULTS: Overall, 683 patients (17.9%) received early interferon-ß therapy. These patients were more severely ill. Adjusted HR for mortality with early interferon-ß was 1.03 (95% CI, 0.82-1.30) in the overall cohort, 0.96 (0.82-1.13) in the PS-matched subcohort, and 0.89 (0.60-1.32) when interferon-ß treatment was analyzed as a time-dependent variable. CONCLUSIONS: In this multicenter cohort of admitted COVID-19 patients, receiving early interferon-ß therapy after hospital admission did not show an association with lower mortality. Whether interferon-ß might be useful in the earlier stages of the disease or specific subgroups of patients requires further research.

Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.

COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.

ESCMID COVID-19 living guidelines: drug treatment and clinical management.

SCOPE: In January 2021, the ESCMID Executive Committee decided to launch a new initiative to develop ESCMID guidelines on several COVID-19-related issues, including treatment of COVID-19. METHODS: An ESCMID COVID-19 guidelines task force was established by the ESCMID Executive Committee. A small group was established, half appointed by the chair, and the remaining selected with an open call. Each panel met virtually once a week. For all decisions, a simple majority vote was used. A long list of clinical questions using the PICO (population, intervention, comparison, outcome) format was developed at the beginning of the process. For each PICO, two panel members performed a literature search with a third panellist involved in case of inconsistent results. Voting was based on the GRADE approach. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: A synthesis of the available evidence and recommendations is provided for each of the 15 PICOs, which cover use of hydroxychloroquine, bamlanivimab alone or in combination with etesevimab, casirivimab combined with imdevimab, ivermectin, azithromycin and empirical antibiotics, colchicine, corticosteroids, convalescent plasma, favipiravir, remdesivir, tocilizumab and interferon ß-1a, as well as the utility of antifungal prophylaxis and enoxaparin. In general, the panel recommended against the use of hydroxychloroquine, ivermectin, azithromycin, colchicine and interferon ß-1a. Conditional recommendations were given for the use of monoclonal antibodies in high-risk outpatients with mild-moderate COVID-19, and remdesivir. There was insufficient evidence to make a recommendation for use of favipiravir and antifungal prophylaxis, and it was recommended that antibiotics should not be routinely prescribed in patients with COVID-19 unless bacterial coinfection or secondary infection is suspected or confirmed. Tocilizumab and corticosteroids were recommended for treatment of severe COVID-19 but not in outpatients with non-severe COVID-19. SCOPE: The aim of the present guidance is to provide evidence-based recommendations for management of adults with coronavirus disease 2019 (COVID-19). More specifically, the goal is to aid clinicians managing patients with COVID-19 at various levels of severity including outpatients, hospitalized patients, and those admitted to intensive care unit. Considering the composition of the panel, mostly clinical microbiologists or infectious disease specialists with no pulmonology or intensive care background, we focus only on pharmacological treatment and do not give recommendations on oxygen supplement/support. Similarly, as no paediatricians were included in the panel; the recommendations are only for adult patients with COVID-19. Considering the current literature, no guidance was given for special populations such as the immunocompromised.

Increased Blood Monocytic Myeloid Derived Suppressor Cells but Low Regulatory T Lymphocytes in Patients with Mild COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may produce a systemic disease, the coronavirus disease-19 (COVID-19), with high morbidity and mortality. Even though we do not fully understand the interaction of innate and adaptive immunity in the control and complications of the viral infection, it is well recognized that SARS-CoV-2 induces an immunodepression that impairs the elimination of the virus and favors its rapid dissemination in the organism. Even less is known about the possible participation of inhibitory cells of the innate immune system, such as the myeloid-derived suppressor cells (MDSCs), or the adaptive immune system, such as the T regulatory cells (Tregs). That is why we aimed to study blood levels of MDSCs, as well as lymphocyte subpopulations, including Tregs, and activated (OX-40+) and inhibited (PD-1) T lymphocytes in patients with mild COVID-19 in comparison with data obtained from control donors. We have found that 20 hospitalized patients with COVID-19 and no health history of immunosuppression had a significant increase in the number of peripheral monocytic MDSCs (M-MDSC), but a decrease in Tregs, as well as an increase in the number of inhibited or exhausted T cells, whereas the number of activated T cells was significantly decreased compared with that from 20 healthy controls. Moreover, there was a significant negative correlation (r = 0.496) between the number of M-MDSC and the number of activated T cells. Therefore, M-MDSC rather than Tregs may contribute to the immunosuppression observed in patients with COVID-19.

Implementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System.

The COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.